What is the efficacy of Leqembi (lecanemab) in treating Alzheimer's disease?

Efficacy of Leqembi (Lecanemab) for Alzheimer's Disease

Leqembi (lecanemab) demonstrates modest efficacy in slowing cognitive decline specifically in early Alzheimer's disease (mild cognitive impairment or mild dementia) with confirmed amyloid pathology, but has significant limitations including lack of efficacy in women and APOE4 carriers, along with potential serious side effects.

Patient Selection and Diagnostic Requirements

• Lecanemab is indicated only for patients with:

  • Confirmed early Alzheimer's disease (mild cognitive impairment or mild dementia)
  • Biomarker-confirmed amyloid beta pathology via PET scan or CSF analysis 1
  • Clinical Dementia Rating (CDR) global score of 0.5 or 1.0
  • Mini-Mental State Examination (MMSE) score between 22-30 2

• Not appropriate for:

  • Advanced Alzheimer's disease (moderate to severe)
  • Patients without confirmed amyloid pathology
  • Patients with normal cognitive testing results (e.g., MMSE 30/30) 1

Clinical Efficacy Evidence

• FDA approval was based on clinical trials showing:

  • Significant reduction in brain amyloid beta plaque (72.5 point reduction in centiloids compared to placebo) 2
  • Slowed cognitive decline measured by composite scores including CDR-SB, MMSE, and ADAS-Cog14 2

• Quality of life outcomes:

  • 49% less decline in EQ-5D-5L (patient-reported)
  • 56% less decline in QOL-AD (patient-reported)
  • 23% less decline in QOL-AD (proxy-reported)
  • 38% less increase in caregiver burden 3

• Long-term modeling suggests potential benefits:

  • Extended duration in milder disease stages
  • Delayed progression to moderate and severe stages by approximately 2-3 years
  • Reduced lifetime probability of institutional care (25% vs 31% with standard care) 4

Important Limitations and Concerns

• Significant efficacy concerns:

  • Did not slow cognitive decline in women, despite women having twice the risk of Alzheimer's disease 5
  • Did not slow cognitive decline in APOE4 carriers (60-75% of Alzheimer's patients)
  • May actually enhance cognitive decline in patients with two APOE4 genes 5

• Safety concerns:

  • Amyloid-Related Imaging Abnormalities (ARIA) with cerebral edema or hemorrhage 1
  • Infusion-related reactions in 26.4% of patients (vs 7% with placebo) 6

Treatment Protocol

• Dosing regimen:

  • 10 mg/kg intravenously every two weeks for first 18 months
  • May transition to 10 mg/kg every four weeks after 18 months 2

• Monitoring requirements:

  • Careful monitoring for ARIA and infusion-related reactions
  • Regular cognitive assessments to determine continued benefit

Comparison to Other Treatments

• Unlike cholinesterase inhibitors (donepezil, rivastigmine, galantamine) which provide symptomatic relief, lecanemab targets underlying amyloid pathology 7

• Traditional cholinesterase inhibitors:

  • Provide modest improvement or temporary stabilization in some patients
  • Approximately 20-35% of patients show meaningful improvement 7
  • Generally better tolerated than newer amyloid-targeting therapies

Clinical Decision Making

• Consider lecanemab only when:

  1. Early Alzheimer's disease is confirmed
  2. Amyloid pathology is confirmed by biomarker testing
  3. Patient understands modest potential benefits and risks
  4. Patient does not have contraindications
  5. Regular monitoring is feasible

• Avoid in patients with:

  • Two APOE4 genes (due to potential worsening)
  • Advanced disease (moderate to severe)
  • Contraindications to monoclonal antibody therapy

Conclusion

While lecanemab shows statistically significant effects on amyloid reduction and modest slowing of cognitive decline in specific patient populations, its clinical meaningfulness remains questionable given its lack of efficacy in women and APOE4 carriers, who represent the majority of Alzheimer's patients. The potential benefits must be carefully weighed against risks, costs, and the limited scope of efficacy.